title: Impaired apoptotic cell clearance in CGD due to altered macrophage programming is reversed by phosphatidylserine-dependent production of IL-4.
abstract: Chronic granulomatous disease (CGD) is characterized by overexuberant inflammation and autoimmunity that are attributed to deficient anti-inflammatory signaling. Although regulation of these processes is complex, phosphatidylserine (PS)-dependent recognition and removal of apoptotic cells (efferocytosis) by phagocytes are potently anti-inflammatory. Since macrophage phenotype also plays a beneficial role in resolution of inflammation, we hypothesized that impaired efferocytosis in CGD due to macrophage skewing contributes to enhanced inflammation. Here we demonstrate that efferocytosis by macrophages from CGD (gp91(phox)(-/-)) mice was suppressed ex vivo and in vivo. Alternative activation with interleukin 4 (IL-4) normalized CGD macrophage efferocytosis, whereas classical activation by lipopolysaccharide (LPS) plus interferon gamma (IFNgamma) had no effect. Importantly, neutralization of IL-4 in wild-type macrophages reduced macrophage efferocytosis, demonstrating a central role for IL-4. This effect was shown to involve 12/15 lipoxygenase and activation of peroxisome-proliferator activated receptor gamma (PPARgamma). Finally, injection of PS (whose exposure is lacking on CGD apoptotic neutrophils) in vivo restored IL-4-dependent macrophage reprogramming and efferocytosis via a similar mechanism. Taken together, these findings support the hypothesis that impaired PS exposure on dying cells results in defective macrophage programming, with consequent efferocytic impairment and has important implications in understanding the underlying cause of enhanced inflammation in CGD.
authors.affiliation: Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: Ruby F
authors.initials: RF
authors.lastname: Fernandez-Boyanapalli
authors.forename: S Courtney
authors.initials: SC
authors.lastname: Frasch
authors.forename: Kathleen
authors.initials: K
authors.lastname: McPhillips
authors.forename: R William
authors.initials: RW
authors.lastname: Vandivier
authors.forename: Brian L
authors.initials: BL
authors.lastname: Harry
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
authors.forename: Donna L
authors.initials: DL
authors.lastname: Bratton
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006105:Granulomatous Disease, Chronic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism* / Q000502:physiology; D019169:Jurkat Cells; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D010718:Phosphatidylserines / Q000494:pharmacology*
chemical_list: D008562:Membrane Glycoproteins; D010718:Phosphatidylserines; D015847:Interleukin-4; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases